In recent years, drug abusers have become an increasingly important risk group for infection with the human immunodeficiency virus (HIV), resulting in complex patterns of brain damage. Brains from drug-dependent HIV patients show vascular injury, myelin damage, and probable neuronal injury. While central stimulants may increase production of cytokines that can lead to myelin injury, the mechanisms of neuronal injury in HIV seropositive (HIV+) drug users are poorly understood. In this context, the main objective of this proposal is to understand better the mechanisms of neurodegeneration in HIV seropositive methamphetamine dependent (METH+) subjects. This project will have a dual function: 1) to provide neuropathological data for the Program Project as a whole; and 2) to define the patterns of neuronal injury in these patients and to elucidate some of the possible mechanisms involved. For this purpose we propose the following Specific Aims: 1) to compare the neuropathological alterations in HIV infected METH+ subjects vs. HIV infected non-methamphetamine dependent subjects (METH-); 2) to determine if methamphetamine dependence alters the patterns of neurodegeneration in HIV infected subjects; 3) to determine mechanisms leading to enhanced methamphetamine-induced excitotoxic neurodegeneration in HIV+ subjects; and 4) to define cellular pathways leading to neuronal cell death and related neuropsychological impairment in HIV+/METH+ subjects. For this purpose, detailed neuropathological analysis as well as studies of neurodegeneration via apoptosis utilizing modern neuropathological methods will be performed in the following groups of individuals: 1) HIV+/METH+ subjects, 2) HIV+/METH-, 3) HIV-/METH+ subjects, and 4) age matched HIV-/METH- controls. This Project proposes a detailed plan to clarify potential mechanisms of neurodegeneration involving the combined use of methamphetamine dependence and HIV. The hypothesis center on the idea that both HIV and methamphetamine converge in mechanisms involving excitotoxicity. The studies will help to elucidate if activation of a specific caspase pathway leads to neurodegeneration in METH+ subjects with AIDS. Furthermore, these studies will help to delineate more clearly the neuronal populations susceptible to degeneration. This is of importance because rapid advances in this field have led to the development of inhibitors of the caspase pathway, that could be potentially used to protect neurons and provide a potential for novel therapeutic approaches.